The leukotrienes are a novel group of biologically-active substances derived from arachidonic acid through the action of the 5-lipoxygenase enzyme system. There are two groups of leukotrienes derived from a common unstable precursor Leukotriene A.sub.4. The first of these are the peptido-lipid leukotrienes, the most important being Leukotrienes C.sub.4 and D.sub.4. These compounds collectively account for the biologically-active material known as the slow reacting substance of anaphylaxis.
The leukotrienes are potent smooth muscle-contracting agents, particularly on respiratory smooth muscle but also on other tissue (e.g., gall bladder). In addition, they promote mucous production, modulate vascular permeability changes and are potent inflammatory agents in human skin. The most important compound in the second group of leukotrienes is Leukotriene B.sub.4, a dihydroxy fatty acid. This compound is a potent chemotactic agent for neutrophils and eosinophils. It also effects other cell types such as lymphocytes and, for example, may modulate the action of T-suppressor cells and natural killer cells. When injected in vivo, in addition to promoting the accumulation of leukocytes, Leukotriene B.sub.4 is also a potent hyperalgesic agent and can modulate vascular permeability changes through a neutrophil-dependent mechanism. See: D. M. Bailey and F. B. Casey, Ann. Rpts. Med. Chem. 17, 203 (1982).
Because the leukotrienes have been implicated in numerous disease states, the inhibition of leukotriene biosynthesis and/or antagonism of leukotriene action, will provide a therapeutic benefit to patients suffering from these disease states. These disease states include, but are not limited to: asthma; allergic conditions, such as allergic rhinitis; skin diseases, including psoriasis and atopic dermatitis; inflammation; gouty arthritis; gall bladder spasms; and cardiovascular disorders, such as angina.
Certain benzo[a]phenothiazine derivatives of general Formula A are known compounds: ##STR2## Some of these compounds have been used (inter alia) as antioxidants, dyes, whitening agents, photosensitizers and polymerization retardants. See for example; T. G. Jackson et al., J. Org. Chem. 32 1190-1194 (1967), J. A. Van Allen et al., J. Organ. Chem. 34 1691-1694 (1969), T. G. Jackson et al. J. Med. Chem. 11 622-623 (1968), N. L. Agarwal et al., Acta Chim. Acad. Sci. Hung. 92 89-97 (1977), R. L. Mital et al., J. Inst. Chem. (India) 49 286-287 (1977), J. P. Tiwari et al., Anorg. Chem., Org. Chem. 33B 214-215 (1978), J. P. Tiwari et al., Indian J. Chem. Sect. B 17B 408-409 (1979), Y. Ueno et al., J. Heterocycl. Chem. 19 167-169 (1982), S. Kikkawa et al., Chemical Abstracts 76 139757q (1972) and French Pat. No. 1,541,977 (1968).
It has been discovered that compounds of the Formula A type and analogs thereof are effective inhibitors of mammalian leukotriene biosynthesis and are thus useful in the treatment of leukotriene-mediated conditions, such as asthma, allergies, inflammation, and the like in mammals, especially in humans.